The long-term objectives are directed to the study of immunotoxic epigenetic mechanisms of carcinogenesis and the development of effective immunotherapeutic preventive or prophylactic means of treatment for cancer and immunodeficiency-related disorders. The specific aims are to determine the effects of a known chemical carcinogen, 3-methylcholantrene (3-MC), on a defined immunoeffector/regulator circuit in the laboratory rat, composed of natural killer cell (NKC), interleukin 2 (IL2), interferon (IFN) and prostaglandin E2 (PGE2), thought to be important in host immunosurveillance to neoplasia. The NKC/IL2/IFN/PGE2 circuit will be clearly characterized in rats of various ages and the interaction of individual components of the circuit, in regard to regulation of NKC activity, will be determined in vitro and in vivo. The in vitro and in vivo effects of 3-MC on components of the circuit will be determined and correlated to tumor incidence and latency, and the sensitivity of 3-MC-induced tumor cells to lysis by rat NKC will be confirmed. Finally, immunotherapeutic treatment regimens, using purified IL2, IFN and a PGE2 inhibitor, will be devised and used to treat rats exposed to 3-MC. It is anticipated that effective in vivo immunotherapeutic treatment regimens using purified endogenous immuno-regulatory cytokines can be devised to prevent or significantly delay spontaneous and chemical-induced tumorigenesis, and eventually may be useful in clinical treatment of immunodeficiency diseases.